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Home , Piracetam, Pramiracetam

Acta Poloniae Pharmaceutica ñ Research, Vol. 62 No. 5 pp. 405-409, 2005 ISSN 0001-6837 Polish Pharmaceutical Society

GENERAL

PIRACETAM ñ AN OLD DRUG WITH NOVEL PROPERTIES?

KATARZYNA WINNICKA1, MARIAN TOMASIAK2 and ANNA BIELAWSKA1

1 Department of Drug Technology, 2 Department of Physical Chemistry, Medical University of Bia≥ystok, 1 KiliÒskiego Str., 15-089 Bia≥ystok, Poland

Abstract: (2-oxo-1--acetamide), the most common of the , is a cyclic derivative of gamma-aminobutyric acid. The treatment with piracetam improves , , brain metabolism, and capacity. Piracetam has been shown to alter the physical properties of the plasma membrane by increasing its fluidity and by protecting the cell against hypoxia. It increases red cell deformability and nor- malizes aggregation of hyperactive . Piracetam is an agent with antithrombotic, neuroprotective and rheological properties. The interaction of this molecule with the membrane phospholipids restores membrane fluidity and could explain the efficacy of piracetam in various disorders ranging from and to and stroke.

Keywords: piracetam, nootropic drugs, inhibitors, rheology

Piracetam (2-oxo-1-pyrrolidineacetamide) (Fig- (12 months) -feeding to rats significantly ure 1) is a cyclic derivative of gamma-aminobutyric increased the formation of (an age-related acid (GABA), obtained after the loss of one molecule waste pigment) in brain cells. Giving high doses of of water followed by ring formation (1). It is the first piracetam to the alcohol-fed rats reduced their lipo- representative of the ìnootropicî drugs (2). fuscin levels significantly below the control levels The term nootropic comes from a Greek word (8). In 1997 it was demonstrated that piracetam meaning ìacting on the mindî. Piracetam was syn- might reduce the neuronal loss following chronic thesized by Giurgea in UCB Laboratories in alcohol consumption (9). Belgium. It has been in clinical use since 1972. Piracetam enhances cognition under conditions Since then other pharmaceutical companies have of hypoxia, and also enhances memory and learning been scrambling to develop their own (10). When piracetam is taken with choline, there is (e.g. vinpocetine, , , oxirac- a synergistic effect that causes a greater improve- etam). ment in memory. Piracetam might be successfully used to treat The specific pharmacological properties of senile dementia, vertigo, sickle cell anemia, and piracetam were reported almost 30 years ago but its numerous other health problems like Alzheimerís was unknown for a long time. disease or stroke (3ñ6). Piracetam might increase Piracetam was firstly tested in a model of ìcentral reading comprehension and accuracy in dyslexic nystagmusî which was sensitive only to anticholin- children (7). It has improved alertness, socialization ergic and antihistaminic drugs (2, 11). The current and IQ in elderly psychiatric patients. Piracetam has use of piracetam in vertigo might be related to this also been used to treat alcoholism. In 1991 Paula- property. The subsequent research, however, Barbosa and colleagues discovered that long-term revealed that piracetam was without anticholinergic or antihistaminic properties (5, 10, 12). Although piracetam is a derivative of the inhibitory GABA, the mechanism of its action is not related to that of GABA. Piracetam has little affinity for glutamate receptors, yet it does have various effects on glutamate neuro- transmission. One subtype of is the AMPA receptor. Micromolar amounts (levels which are achieved through oral piracetam intake) Figure 1. Structure of piracetam (2-oxo-1-pyrrolidineacetamide) ñ of piracetam enhance the efficacy of AMPA- prototypical nootropic; a cyclic derivative of GABA. induced calcium influx in brain cells. Piracetam also

405 406 KATARZYNA WINNICKA et al. increases the maximal density of AMPA receptors increased blood flow in impaired brain regions. in synaptic membranes from rat cortex due to the Whereas the effect of physiotherapy for the recruitment of a subset of AMPA receptors which improvement of sensorimotor deficits is unchal- do not normally contribute to synaptic transmission lenged, the efficacy of speech therapy is still ques- (12). At micromolar levels piracetam potentiates tionable/unclear. Whether the rehabilitation can be potassium-induced release of glutamate from rat enhanced by adjuvant pharmacotherapy in patients hippocampal nerves (12). with cerebral disorders is also a matter of specula- Piracetam is generally reported to have mini- tion (20ñ22). First trials were started in the 1940s mal or no side effects. It is interesting to note, how- and concerned various agents in various neurolog- ever, that piracetamís occasionally reported side ical disorders (23ñ25). Since piracetam improves effects of , , agitation, learning and memory, Kessler et al. investigated in and are identical to the symptoms of exces- a double-blind, placebo-controlled study whether sive /glutamate neuroactivity. In spite piracetam improves language recovery in post- of these effects, piracetam is generally not consid- stroke aphasia (26). They found that piracetam ered to be a significant agonist or inhibitor of the significantly improves activated blood flow and synaptic action of most . The facilitates rehabilitation of poststroke aphasic piracetam-type nootropic drugs might exert their patients (26). Piracetam as an adjuvant to speech effect on some species of molecules present in the therapy improves recovery of various language plasma membrane. It would seem that they act as functions, and this effect is accompanied by a sig- potentiators of an already present activity, rather nificant increase of task-related flow activation in than possessing any neurotransmitter-like activity of eloquent areas of the left hemisphere (26). their own (12). Thus, piracetam is not prone to the However, the mechanism by which piracetam often serious side effects of drugs which directly enhances recovery from aphasia is still a matter of amplify or inhibit neurotransmitter action, e.g. speculation. Since infracted tissue cannot regener- MAO inhibitors, selective serotonin reuptake ate, recovery from postroke aphasia must involve inhibitors, tricyclic antidepressants, or ampheta- regions outside the morphologically damaged area mines. that probably take over language functions lost in It was found that piracetam instead facilitates acute stroke. interhemispheric transfer, enhances the cerebral resistance to noxious stimuli like hypoxia and ñ derivative of piracetam with antie- improves learning and other cognitive functions pileptic properpies under normal conditions (13, 14). However, the Levetiracetam is the S-enantiomer of α-ethyl- improvement of these functions is much more pro- 2-oxo-1-pyrrolidineacetamide (Figure 2). nounced when brain function is impaired by a vari- Although piracetam might be useful in ety of noxious stimuli (e.g. hypoxia, aging, cerebral myoclonus and potentiates action of injuries). The in vivo experiments indicate that the various antiepileptic drugs (28,29), it was not previ- cognition-enhancing properties of piracetam are ously used per se in epilepsy. Levetiracetam, how- usually more significant in older animals (15, 16). It ever, was approved for the add on treatment of par- suggests that the mechanism of action of the tial epilepsy, both in United States and in Europe nootropic drugs is associated with biochemical alter- (27). Levetiracetam has antiepileptogenic and neu- ations in the aged brain. Therefore nootropics might probably restore or counteract these biochemical changes. Reduced fluidity of brain cell membranes (probably caused by higher membrane concentra- tions of saturated fatty acids) represents mechanism associated with functional alterations in the aged brain (17) and might be responsible for deficits or dysfunctions of mechanisms of signal transduction (18,19).

Piracetam in aphasia Most patients after the ischemic stroke regain some of the lost functions. The improvement of Figure 2. Levetiracetam is a pyrrolidone derivative and is chemi- sensorimotor function is accompanied by an cally designated as (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide (27). Piracetam ñ an old drug with novel properties? 407

Figure 3. Molecular mechanisms of the inhibition of platelet responses by piracetam, acetylsalicylic acid, ticlopidine, dipiridamol and GPIIb/IIIa blockers.

There is some evidence that piracetam acts on platelets as an antagonist of thromboxane A2 or as an inhibitor of thromboxane A2 synthetase together with a reduction in the plasma level of von Willebrandís factor (36). Piracetam also possesses a rheological effect related to its action on cell membrane deformability (37). AA ñ Arachidonic acid; AC ñ Adenylyl cyclase; ADP ñ Adenosine diphosphate; βTG ñ β-thromboglobulin; COX ñ Cyclooxygenase; DAG

ñ Diacylglycerol; GPIIb/IIIa ñ Glycoprotein IIb/IIIa; Gq, Gs ñ G-proteins; 5-HT ñ Serotonin; IP3 ñ Inositol-1,4,5-triphosphate; P2Y1, 12 ñ

ADP-receptor; PAF ñ Platelet activating factor; PF4 ñ Platelet factor 4; PG G2, PG H2, PG I2, PG E2 ñ Prostaglandins G2, H2, I2, E2; PIP2 ñ Phosphatidylinositol-4,5-diphosphate; PKCa, PKCi ñ Protein kinase C (active and inactive, respectively); PLA2 ñ Phospholipase A2;

PLCβ, γ ñ Phospholipase Cβ, γ; TxA2 ñ Thromboxane A2

roprotective effects, with the potential to slow or Piracetam in stroke arrest disease progression (30). It may benefit Piracetam has been reported to increase com- myoclonus in progressive myoclonic epilepsy (31). promised regional cerebral blood flow in patients Although the mechanism of action of levetiracetam with acute stroke and, given soon after onset, to is not completely understood, it is suggested that a improve clinical outcome (33, 34). It could be due reduction of potassium currents in neurons may con- to the modification of rheological properties of tribute to its antiepileptic effect(s) (32). circulating blood by changing platelet responses (aggregation and adhesion) and beneficial effect Piracetam in Alzheimerís disease on deformability leading to a puta- Hippocampal membranes of patients with tive reduction of ADP release by damaged ery- Alzheimerís disease show decreased fluidity which throcytes (35ñ37). Experimental data suggest that differ from age-specific membrane alterations. the efficacy of piracetam in secondary stroke pro- Clinical data suggest that long-term piracetam treat- phylaxis is not as good as that of acetylsalicylic ment appears to slow the progression of Alzheimerís acid (ASA) but that piracetam is better tolerated disease, which was proposed to be explained by (38). Therefore, piracetam might be an alternative restoration of membrane fluidity (19). for secondary stroke prophylaxis in patients who 408 KATARZYNA WINNICKA et al. cannot be treated by ASA or other antiplatelet 2. Giurgea C.: Curr. Develop. Psychopharmacol. drugs. 3, 221 (1976). 3. Benesova O.: Drugs Aging 4, 285 (1994). Piracetam and platelets 4. Croisile B., Trillet M., Fondarai J., Laurent B., Modification of platelet function including Mauguiare F., Billardon M.: Neurology 43, 301 inhibition of platelet aggregation by piracetam is (1993). known for over 20 years (35). However, the mode of 5. Vernon M.W., Sorkin E.M.: Drugs Aging 1, 17 its action is still debated (36ñ39). (1991). Piracetam normalizes hyperactive platelets in 6. Skondia V., Kabes J.: J. Int. Med. Res. 13, 185 various disorders including acute stroke (33, 34), (1985). transient cerebral ischemic attacks, Raynaudís phe- 7. DeBerdt W.: Life Sci. 55, 2057 (1994). nomenon and diabetes mellitus (36). Platelet- 8. Paula-Barbosa M.: Alcoholism Res. 15, 834 inhibitory effects have been suggested to be due to a (1991). reduced responsiveness to ADP or to inhibition of 9. Cadete-Leite A., Brandao F., Andrade J., thromboxane A2 synthesis (37, 40). Piracetam was Ribeiro-da-Silva A., Paula-Barbosa M.: Alco- also reported to have a direct effect on the vascular hol Alcohol. 32, 471 (1997). wall, stimulating prostacyclin production in 10. Noble S., Benfield P.: CNS Drugs 9, 497 with an concomitant reduction of von (1998). Willebrandís factor release from WeibelñPalade 11. Giurgea C.: Drug Dev. Res. 2, 441 (1982). bodies (37). 12. Gouliaev A.H., Senning A.: Brain Res. Rev. 19, The doses necessary to achieve rheological 180 (1994). and/or antiplatelet effects are about 2ñ4 times high- 13. Nalini K., Karanth K.S., Rao A., Aroor A.R.: er than the doses required to obtain nootropic effects Pharmacol. Biochem. 42, 859 (1992). (35). However, even at these elevated doses, pirac- 14. Soerensen J.B., Smith D.F.: J. Neural Transm. etam is well tolerated and only few adverse effects 6, 139 (1993). have been recorded in human subjects (5, 10). 15. Roux S., Hubert I., Lenegre A., Milinkevitch The rheological properties of piracetam are D., Porsolt R.D.: Pharmacol. Biochem. Behav. thought to be related to plasma membrane alterations 49, 683 (1994). such as lipid structure (37). Piracetam incorporates 16. Muller W.E., Koch S., Scheuer K., Rostock A., within membranes at the level of the polar heads of the Bartsch R.: Biochem. Pharmacol. 53, 135 phospholipids. This interaction with the membrane (1997). phospholipids restores membrane fluidity and could 17. Ghosh C., Dick R.M., All S.F.: Neurochem. Int. explain the pharmacological properties of piracetam. 23, 479 (1993). The observation that piracetam binds to the polar head 18. Miyamoto A., Araiso T., Koyama T., Ohshika groups of membrane bilayers and induces changes in H.: J. Neurochem. 55, 70 (1990). membrane structure can explain that this drug works 19. Muller W.E., Eckert G.P., Eckert A.: Pharma- not only in the brain but also at the level of blood cells copsychiatry 32, 2 (1999). (19). Its activity is much more pronounced when 20. Ferro J.M., Mariano G., Madureira S.: Cere- membranes are impaired (e.g. in aging). brovasc. Dis. 9, 6 (1999). Since changes at the level of the platelet mem- 21. Small S.L.: Stroke 25, 1282 (1994). brane seem to be involved into the cascade of events 22. Wallesch C.W., Muller U., Hermann M.: CNS leading to platelet adhesion and aggregation, this Drugs 7, 203 (1997). membrane-modifying effect might be the primary 23. Linn L.: Arch. Neurol. Psychiatry 58, 357 mechanism of action of piracetam (Figure 3). This (1947). mechanism would differentiate piracetam from 24. Bachman L., Morgan A.: Aphasiology 2, 225 other drugs used to inhibit platelet aggregation such (1988). as ASA, ticlopidine or tirofiban. Ticlopidine, how- 25. Jacobs D.H., Shuren J., Gold M., Adair J.C., ever, as a lipophilic drug might also alter the fluidi- Bowers D., Williamson D.J.G., Heilman K.M.: ty of platelet membrane. Neurocase 2, 83 (1996). 26. Kessler J., Thiel A., Karbe H., Heiss W.D.: REFERENCES Stroke 31, 2112 (2000). 27. Shorvon S.D., van Rijckevorsel K.: J. Neurol. 1. Strubbe J.H., Cyprisiak E.: Rev. Indust. Chim. Neurosurg. Psych. 72, 426 (2002). Belge 32, 112 (1967). 28. Chaudhry H.: Curr. Ther. Res. 9, 355 (1992). Piracetam ñ an old drug with novel properties? 409

29. Fedi M., Reutens D., Dubeau F., Andermann E., 36. Evers S., Grotemeyer K.H.: Pharmacopsychia- DíAgostino D., Andermann F.: Arch. Neurol. try 32, 44 (1999). 58, 781 (2001). 37. Moriau M., Crasborn L., Lavenne-Pardonge E., 30. Ben-Menachem E.: Expert Opin. Pharmacother. von Frenckell R., Col-Debeys C.: Arzneimittel- 4, 2079 (2003). forschung 43, 110 (1993). 31. Crest C., Dupont S., Leguern E., Adam C., 38. Grotemeyer K.H., Evers S., Fischer M., Hus- Baulac M.: Neurology 62, 640 (2004). stedt I.W.: J. Neurol. Sci. 181, 65 (2000). 32. Madeja M., Margineanu D.G., Gorji A., Siep E., 39. Peuvot J., Schanck A., Deleers M., Brasseur R.: Boerrigter P., Klitgaard H., Speckmann E.J.: Biochem. Pharmacol. 50, 1129 (1995). Neuropharmacology 45, 661 (2003). 40. Bick R.L., Thromb. Haemost. 46, 67 (1981). 33. Orgogozo J.M.: Stroke 32, 1449 (2001). 34. Ferguson J.J.: Circulation 94, 1195 (1996). Received: 24.08.05 35. Bick R.L.: Lancet 2, 752 (1979).